Erythropoietin receptor peptide formulations and uses

Abstract

The present invention relates to novel uses of peptide compounds that are agonists of the erythropoietin receptor (EPO-R). The invention also relates to methods of using such peptide compounds to treat disorders associated with insufficient or defective red blood cell production, including chemotherapy induced anemia. Pharmaceutical compositions, which comprise the peptide compounds of the invention, are also provided. Also provided are kits and articles of manufacture comprising such compounds.

1 . A method of treating a disorder characterized by deficiency of erythropoietin or a low or defective red blood cell population in a patient who is undergoing, has undergone, or will undergo, chemotherapy for lung, breast or prostate cancer, comprising administering to the patient a therapeutically effective amount of a compound comprising:
 (a) a first and second peptide monomer comprising the amino acid sequence (AcG)GLYACHMGPIT(1-nal)VCQPLR (SEQ ID NO: 14);   (b) a linker moiety covalently bonding the first peptide monomer to the second peptide monomer; and   (c) a spacer moiety covalently joining the linker moiety and a poly(ethylene glycol) (PEG) moiety, said PEG moiety comprising a linear, unbranched PEG having a molecular weight from about 10,000 Daltons to about 60,000 Daltons.   
     
     
         2 . The method of  claim 1 , wherein the amino acid sequence of the first and/or second peptide monomer additionally comprises (MeG), K, or (MeG)K at the C-terminus. 
     
     
         3 . The method of  claim 2 , wherein the amino acid sequence of the first and/or second peptide monomer is (AcG)GLYACHMGPIT(1-nal)VCQPLRK (SEQ ID NO: 1). 
     
     
         4 . The method of  claim 2 , wherein the amino acid sequence of the first and/or second peptide monomer is (AcG)GLYACHMGPIT(1-nal)VCQPLR(MeG) (SEQ ID NO: 3). 
     
     
         5 . The method of  claim 2 , wherein the amino acid sequence of the first and/or second monomer is (AcG)GLYACHMGPIT(1-nal)VCQPLR(MeG)K (SEQ ID NO: 2). 
     
     
         6 . The method of  claim 1 , wherein two cysteine residues of the first and/or second peptide monomer are bonded together through a disulfide bridge. 
     
     
         7 . The method of  claim 1 , wherein the linker moiety comprises an amide derivative of a lysine residue. 
     
     
         8 . The method of  claim 7 , wherein the amide derivative of a lysine residue is covalently bonded through the nitrogen atom of its side chain. 
     
     
         9 . The method of  claim 1 , wherein the linker moiety is defined by the formula: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 1 , wherein the spacer moiety is defined by the formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 1 , wherein the compound is further defined by the formula: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts, hydrates, solvates, tautomers, acetals, ketals, prodrugs, or optical isomers thereof. 
     
     
         12 . The method of  claim 11 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof, and substantially free from other optical isomers thereof. 
     
     
         13 . The method of  claim 1 , wherein the PEG moiety has a molecular weight from about 10,000 Dalton to about 50,000 Daltons. 
     
     
         14 . The method of  claim 13 , wherein the PEG moiety has a molecular weight from about 20,000 Daltons to about 40,000 Daltons. 
     
     
         15 . The method of  claim 1 , wherein the disorder is anemia. 
     
     
         16 . The method of  claim 15 , wherein the disorder is chemotherapy-induced anemia. 
     
     
         17 . The method of  claim 1 , wherein the patient is undergoing, has undergone, or will undergo, chemotherapy for lung cancer. 
     
     
         18 . The method of  claim 17 , where the lung cancer is non-small cell lung cancer. 
     
     
         19 . The method of  claim 1 , wherein the patient is undergoing, has undergone, or will undergo, chemotherapy for prostate cancer. 
     
     
         20 . The method of  claim 1 , wherein the patient is undergoing, has undergone, or will undergo, chemotherapy for breast cancer. 
     
     
         21 . The method of  claim 1 , wherein the patient is a primate. 
     
     
         22 . The method of  claim 1 , wherein the patient is a human. 
     
     
         23 . The method of  claim 1 , further comprising identifying a patient in need of treatment. 
     
     
         24 . The method of  claim 1 , wherein the compound is administered locally. 
     
     
         25 . The method of  claim 1 , wherein the compound is administered systemically. 
     
     
         26 . The method of  claim 25 , wherein the compound is administered intravenously, intra-arterially, intramuscularly, intraperitoneally, subcutaneously or orally. 
     
     
         27 . The method of  claim 1 , wherein the therapeutically effective amount is a dosage from about 0.01 milligram to about 1,000 milligram of the compound per kilogram of body weight of the patient. 
     
     
         28 . The method of  claim 27 , wherein the therapeutically effective amount is a dosage from about 0.025 milligram to about 0.5 milligram of the compound per kilogram of body weight of the patient. 
     
     
         29 . The method of  claim 27 , wherein the therapeutically effective amount is a dosage from about 0.025 milligram to about 0.2 milligram of the compound per kilogram of body weight of the patient. 
     
     
         30 . The method of  claim 27 , wherein the therapeutically effective amount is a dosage from about 0.05 milligram to about 0.1 milligram of the compound per kilogram of body weight of the patient. 
     
     
         31 . The method of  claim 27 , wherein the therapeutically effective amount is administered in a single dose per day. 
     
     
         32 . The method of  claim 27 , wherein the therapeutically effective amount is administered in two or more doses per day. 
     
     
         33 . The method of  claim 27 , wherein the therapeutically effective amount is administered once every 3 to 4 weeks. 
     
     
         34 . A pharmaceutical composition for preventing or treating a disorder characterized by deficiency of erythropoietin or a low or defective red blood cell population in a patient who is undergoing, has undergone, or will undergo, chemotherapy for lung, breast or prostate cancer, which comprises a compound comprising:
 (a) a first and second peptide monomer comprising the amino acid sequence (AcG)GLYACHMGPIT(1-nal)VCQPLR (SEQ ID NO: 14);   (b) a linker moiety covalently bonding the first peptide monomer to the second peptide monomer; and   (c) a spacer moiety covalently joining the linker moiety and a poly(ethylene glycol) (PEG) moiety, said PEG moiety comprising a linear, unbranched PEG having a molecular weight from about 10,000 Daltons to about 60,000 Daltons.